PROSTAGLANDIN-H SYNTHASE-2 IS EXPRESSED ABNORMALLY IN HUMAN COLON-CANCER - EVIDENCE FOR A TRANSCRIPTIONAL EFFECT

Evidence from epidemiological studies, clinical trials, and animal exp eriments indicates that inhibitors of prostaglandin synthesis lower th e risk of colon cancer. We tested the hypothesis that abnormal express ion of prostaglandin H synthase 2 (PHS-2), which can be induced by onc ogenes and tumor promoters, occurs during colon carcinogenesis by exam ining its level in colon tumors. Human colon cancers were found to hav e an increased expression of PHS-2 mRNA compared with normal colon spe cimens from the same patient (n = 5). In situ hybridization showed tha t the neoplastic colonocytes had increased expression of PHS-2 (n = 4) . Additionally, five colon cancer cell lines were shown to express hig h levels of PHS-2 mRNA even in the absence of a known inducer of PHS-2 . To study the basis for this increased gene expression, we transfecte d a colon cancer cell line, HCT-116, with a reporter gene containing 2 .0 kb of the 5' regulatory sequence of the PHS-2 gene. Constitutive tr anscription of the reporter gene was observed, whereas normal control cell lines transcribed the reporter only in response to an exogenous a gonist. We conclude that PHS-2 is transcribed abnormally in human colo n cancers and that this may be one mechanism by which prostaglandins o r related compounds that support carcinogenesis are generated.